This proposal has as its central purpose the establishment of a long-term research effort into the molecular pathology of cellular aging of the brain. We seek to understand the role of a major class of neuronal proteins, the fibrous proteins, both in normal aging and in the pathogenesis of the late-life dementias. By far the most common neuronal degenerations that accompany aging are presenile and senile dementia. These age-related disorders, now classified together under the term Alzheimer's Disease, have as their most widespread and specific pathological finding and abnormality of the neuronal fibrous proteins, seen both in the perikarya and the neuropil. Fibrillary degeneration of neurons and their processes is associated not only with progressive loss of intellect but represents the most important structure abnormality in the brains of healthy individuals of great age. We are isolating and biochemically characterizing the filamentous proteins which are found in Alzheimer's Disease and comparing them to analogous proteins in the brains of elderly patients with normal mentation and in an experimental model of neurofibrillary disease, aluminum encephalopathy (AE). Neuronal perikarya have been isolated in bulk from diseased human cortex and from AE and show good preservation of normal cytoplasmic organelles and paired helical filaments by lighted electron microscopy. Analytical protein separation has shown selective and distinct protein changes in neurons from Alzheimer's Disease and from Huntington's Disease as well as in AE. Biochemical and cell biological techniques are being used to characterize such proteins and establish their role in the pathogenesis of senile dementia and neuronal aging.